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Short-Course Isoniazid Plus Rifampin Effective for Latent TB in Children
A 3- or 4-month regimen of isoniazid plus rifampin is at least as effective as a 9-month course of isoniazid monotherapy in treating latent TB in children, according to results of a prospective, randomized trial.

As noted in the report in the September 15th issue of Clinical Infectious Diseases, dual therapy may be preferable because the shorter duration of treatment was associated with better compliance.

"Tuberculosis remains a major public health problem, and infectious diseases specialists should continue to explore new ideas on the line of prevention, diagnosis and management of infected patients," senior author Dr. Maria N. Tsolia told Reuters Health. "We feel that this study is assisting in this direction, especially because it involved a pediatric population and the results were not extracted from adult studies."

The American Academy of Pediatrics recommends 9 months of isoniazid chemoprophylaxis for children and adolescents with latent TB, the authors point out. The British Thoracic Society recommends 3 months treatment with isoniazid plus rifampin.

Dr. Tsolia and her associates at the TB clinic of Athens University School of Medicine evaluated the different regimens in children ages 12 months to 14 years who were asymptomatic and had positive tuberculin skin test results. Chest x-rays were normal or indicative of inactive lesions.

Over an 11-year period, patients in groups of 220 to 238 were randomly assigned to different treatment protocols:

* Isoniazid monotherapy, 10 mg/kg daily (maximum dose 300 mg) for 9 months versus isoniazid plus rifampin 10 mg/kg daily (maximum 600 mg) for 4 months (conducted between 1995-1998).

* Isoniazid plus rifampin for 4 months versus 3 months (1999-2002).

Follow-up lasted until the end of 2005 (3 to 11 years).

Compliance with treatment was determined based on urine strips that detect isoniazid metabolites and the presence of rifampin, as well as attendance at all follow-up visits.

Of 926 patients enrolled in the study, compliance was moderate to excellent in 91.8%, the report indicates.

Poor compliance was significantly more common among patients assigned to the 9-month isoniazid treatment (13.8%) than among those assigned to dual therapy (5.0% - 7.6%).

"All parents were advised to supervise their children during drug administration," Dr. Tsolia added. "We observed that children over 10 years of age showed signs of reduced compliance after the 4th month of treatment on the monotherapy group, emphasizing the fact that 'the shorter the duration of therapy, the better the compliance'."

At the 4-month evaluation, radiological evidence of possible active disease, such as hilar adenopathy or parenchymal lesions, was more common in the monotherapy group (24%) than in the short-course groups (11.0% - 13.6%).

"Radiologic TB can evolve into clinical TB if left untreated," Dr. Tsolia noted. Patients with radiologic TB were treated for 9 months with both agents.

One explanation for the disparities in outcomes, Dr. Tsolia and associates suggest, is that "combination treatment with two bactericidal drugs produces a more rapid reduction in bacterial load; this may explain why fewer radiographic changes were seen on follow-up."

Adverse events included nausea and epigastric pain (6.5% in the monotherapy group and 0.7% in the dual therapy groups) and transient increases in liver enzyme levels (6% and 1.2%, respectively). A few of those treated with rifampin plus isoniazid also reported an occasional maculopapular rash (1.3%) or a photosensitivity reaction (0.7%).

Still, there was no progression from latent TB to clinical, symptomatic disease at the end of study and during follow-up, the investigators note. Treatments were safe and well tolerated, there being no serious drug-related adverse events or discontinuation or modification of treatment required.

The authors state: "Short-course regimens prevent progression of infection to disease and are effective against subclinical disease, even in patients who are at higher risk, such as children aged <5 years, patients with reinfection, and persons who have a high bacterial load associated with intrafamilial transmission of infections."

"We strongly believe that the 3-4 month short course prophylactic treatment with isoniazid and rifampin is safe and effective," Dr. Tsolia said. She noted that she and her associates are currently using this regimen to treat all their patients with latent TB, then following them for 3 more years.

"The only exceptions," she said, "would be the development of serious rifampin side effects (which are very rare in children, and never occurred in our patients); simultaneous administration of other medications that may interact with rifampin (such as highly active antiretroviral therapy for treatment of HIV); or known resistance to rifampin."


Sources
Clin Infect Dis. 2007;45:715-722
The Effectiveness of a 9-Month Regimen of Isoniazid Alone versus 3- and 4-Month Regimens of Isoniazid plus Rifampin for Treatment of Latent Tuberculosis Infection in Children: Results of an 11-Year Randomized Study
Nikos P. Spyridis, Panayotis G. Spyridis, Anna Gelesme, Vana Sypsa, Mina Valianatou, Flora Metsou, Dimitris Gourgiotis, and Maria N. Tsolia1

Reuters Health

Medscape.com
Short-Course Isoniazid Plus Rifampin Effective for Latent TB in Children
News Author: Karla Gale, MS - CME Author: Désirée Lie, MD, MSEd


Questions
A. A 12-year-old boy has latent TB infection diagnosed. According to the current study, treatment with 4 months of combined isoniazid and rifampin vs 9 months of isoniazid is most likely to be associated with which of the following outcomes?
1. Higher drop-out rate
2. Higher medication compliance rate
3. More serious adverse events
4. Greater likelihood of nausea

B. Which of the following statements best describes the efficacy of the short combined isoniazid and rifampin regimen vs the long isoniazid regimen for latent TB infection in children?
1. Similar efficacy for radiologic TB
2. Greater efficacy for clinical TB
3. Greater efficacy for radiologic TB
4. Greater efficacy for both radiologic and clinical TB


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